Notch3/VEGF-A axis is involved in TAT-mediated proliferation of pulmonary artery smooth muscle cells: Implications for HIV-associated PAH.
Notch3/VEGF-A axis is involved in TAT-mediated proliferation of pulmonary artery smooth muscle cells: Implications for HIV-associated PAH.
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DOI：
10.1038/s41420-018-0087-9
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发表时间：
2018
影响因子：
7
通讯作者：
Buch S
中科院分区：
文献类型：
--
作者：
Guo ML;Kook YH;Shannon CE;Buch S
肺动脉高压（PAH）的发病率是在HIV（+）个体中观察到的一种重要的共病。肺动脉平滑肌细胞（PASMC）-调节血管直径的动脉血管壁的关键组分，在HIV感染个体的肺中表现出增殖和肥大增加，强调了这些细胞在HIV相关PAH发病机制中的作用。虽然有几种途径与PASMC的增殖增强有关，但HIV相关的PASMC增殖的详细分子机制仍然难以捉摸。在本研究中，我们试图研究HIV蛋白转录反式激活因子（达特）介导的PASMCs增殖的影响。与早期的研究结果一致，我们的研究结果也证明了TAT介导的人PASMCs增殖。我们发现了一种新的Notch 3信号通路在TAT介导的PASMCs增殖中的激活。使用药理学方法（γ-分泌酶抑制剂，DAPT）和遗传方法（Notch 3 siRNA）进一步验证了Notch 3途径。血管内皮生长因子A（VEGF-A）被鉴定为Notch激活后诱导的新型下游分子。在存档的猴免疫缺陷病毒（SIV）感染的猴肺组织中进一步验证了体外研究的结果。与SIV（-）对照组相比，SIV感染猕猴的肺中Notch 3信号的激活增加，VEGF-A的表达也增加。总之，我们证明了HIV-TAT通过Notch 3/VEGF-A轴增加PASMCs的增殖。因此，靶向Notch 3/VEGF-A轴可以被认为是治疗HIV相关PAH的潜在治疗方法。
The incidence of pulmonary arterial hypertension (PAH) is a significant co-morbidity observed in HIV (+) individuals. Pulmonary artery smooth muscle cells (PASMCs)—key components of the arterial vessel wall that regulate vessel diameter, demonstrate increased proliferation and hypertrophy in the lungs of HIV infected individuals, underscoring the role of these cells in the pathogenesis of HIV-associated PAH. While several pathways have been implicated in enhanced proliferation of PASMCs, detailed molecular mechanism(s) underlying HIV-associated PASMC proliferation still remain elusive. In the current study, we sought to investigate the effects HIV protein transactivator of transcription (TAT)-mediated proliferation on PASMCs. In agreement with earlier findings, our results also demonstrated TAT-mediated proliferation of human PASMCs. We identified activation of a novel Notch3 signaling pathway in TAT-mediated proliferation of PASMCs. Further validation of the Notch 3 pathway was demonstrated using both pharmacological (γ-secretase inhibitor, DAPT), as well as genetic approaches (Notch3 siRNA). Vascular endothelial growth factor A (VEGF-A) was identified as a novel downstream molecule that was induced following Notch activation. Findings from in vitro studies were further validated in archived simian immunodeficiency virus (SIV)-infected monkey lung tissues. There was increased activation of Notch3 signaling as well as enhanced expression of VEGF-A in the lungs of SIV-infected macaques compared with the lungs of SIV(−) controls. Taken together, we demonstrated that HIV-TAT increased the proliferation of PASMCs via the Notch3/VEGF-A axis. Targeting the Notch3/VEGF-A axis could thus be considered a potential therapeutic approach for the treatment of HIV-associated PAH.
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影响因子：
5.8
作者：
Mermis J;Gu H;Xue B;Li F;Tawfik O;Buch S;Bartolome S;O'Brien-Ladner A;Dhillon NK
通讯作者：
Dhillon NK
DOI：
10.1152/ajplung.00200.2004
发表时间：
2005-08-01
影响因子：
4.9
作者：
Liu, K;Chi, DS;Krishnaswamy, G
通讯作者：
Krishnaswamy, G
DOI：
10.1016/j.bbamcr.2005.06.013
发表时间：
2005-09-10
影响因子：
5.1
作者：
Bernardini, D;Ballabio, E;Maier, JAM
通讯作者：
Maier, JAM
影响因子：
24.3
作者：
Dabral, Swati;Tian, Xia;Schermuly, Ralph Theo
通讯作者：
Schermuly, Ralph Theo
影响因子：
5.3
作者：
Fan, Yan;Gao, Xiang;He, Johnny J.
通讯作者：
He, Johnny J.